Depression and anxiety are highly prevalent (25-40%) in individuals with Parkinson disease (PD) and are the main cause of decreased quality of life in this population. Admissions to nursing homes and caregiver strain are influenced most by the psychiatric comorbidities of PD, not the cardinal motor symptoms of PD. Thus, understanding the neural circuits and predictive variables for the development of depression or anxiety in PD is an important area of research with significant clinical implications. One method for investigating the vulnerability of neural circuits underlying mood complications in PD is to study individuals treated with deep brain stimulation of the subthalamic nucleus (DBS STN). Optimal treatment with DBS STN has significant motor benefits for many PD patients. However, DBS STN can have unintended consequences on mood, perhaps due in part to the location of the active contact(s) within the functionally heterogeneous STN. It is known that anatomical pathways connect ventromedial STN to emotional systems (e.g. ventral pallidum, ventral striatum, anterior cingulate) and dorsal STN to motor systems in the brain (e.g. putamen, primary motor cortex). Direct tests of the hypothesis that stimulation of ventromedial STN influences acute changes in mood more than dorsal STN have not yet been done. In addition, the significance of any acute mood changes in response to DBS STN for understanding the neuropathophysiology of chronic, clinically significant mood disorders in PD is not known. We will use DBS STN and a novel, validated method for locating the site of contacts within the STN to address questions about the neural circuitry underlying acute and chronic mood dysfunction in Parkinson's disease. These methods provide a unique opportunity to map the relationship between STN regions (e.g. dorsal vs. ventromedial; left vs. right) and mood responses. In addition, we will determine if acute responses to stimulation of emotional areas of the STN are influenced by past or predictive of future clinical mood disorders. These experiments cannot be addressed in normal volunteers or in nonhuman animals. In addition to the direct clinical relevance for PD patients both with and without DBS, a better understanding of the neural circuitry involved in mood changes may provide useful information for others as well (e.g. individuals with altered basal ganglia functioning such as Huntington's disease, patients with non- PD major depression or anxiety). PUBLIC HEALTH RELEVANCE Depression and anxiety are highly prevalent (25-40%) in individuals with Parkinson disease (PD) and are the main cause of decreased quality of life in this population. This research will help to determine the neural circuitry involved in mood changes in PD and may provide useful information for other populations as well (e.g. individuals with altered basal ganglia functioning such as Huntington's disease, non-PD patients with major depression or anxiety). [unreadable] [unreadable] [unreadable]